The present invention relates to methods and devices for treating malignant tumors. More specifically the present invention relates to methods and devices for killing tumor cells by creating free radicals in a tumor, and extending the lifetime and modifying the reaction kinetics of the free radicals by exposing them to a magnetic field.
A central problem in cancer treatment is that of preserving healthy tissue while destroying cancerous tissue. Although radiation therapy generally involves the focusing of radiation on a tumor, at least some healthy tissue generally is located in the irradiated field. This healthy tissue is exposed to and to some degree damaged by the radiation. In chemotherapy healthy tissue is exposed to the chemotherapy agent and may be damaged.
Moreover, research has shown that much of the effect of radiation therapy and a substantial component of some approaches to chemotherapy are mediated by free radical effects in tumor tissue. The mechanisms whereby free radicals produce tumor cell death include direct enzymatic effects, DNA damage and induction of apoptotic pathways.
Our understanding of the physics and chemistry of free radicals and paired radicals has gradually increased over the past ten years. A free radical is any chemical species capable of an independent existence that has an unpaired electron in its valence shell. The presence of an unpaired electron in the valence shell causes free radicals to be paramagnetic and exhibit magnetic properties when exposed to a magnetic field.
Free radicals may be formed by any of several mechanisms including but not limited to: Ultraviolet induced homolytic fission as may be encountered in laser ablation therapy of tumors; Specific chemical reactions as encountered with pharmacological chemotherapy e.g. bleomycin; Ionizing radiation as the result of external beam irradiation, antibody directed or site selective radio-nucleotide administration or through implantation radiotherapy e.g. prostatic brachyotherapy; Thermal induction as in hyperthermic therapy; or Ultrasound induced acoustic cavitation.
Free radicals once generated may recombine. The biologic effects of free radicals in tissue are determined by the net reactive fraction namely the “escape” population that does not recombine rapidly. Factors, which influence pair recombination, include the viscosity of the reaction environment, temperature, bystander effects and the quantum state of the free radical. The quantum state of the free radical is defined by the applicable Schrodinger equation (H.PSI.=E.PSI.) where H is a Hamiltonian operator and .PSI. are sets of wave functions (Eigenfunctions). The Eigenfunctions are defined by a set of four quantum numbers: n—the principal quantum number, 1—the orbital quantum number, M.sub.1—the magnetic quantum number and M.sub.s—the spin quantum number. Of particular significance to this discussion is the spin quantum number.
The spin quantum number for an unpaired orbital electron can assume one of two values either +½ or −½. The wave distribution function determined by spin quantization is a vector quantity and subject to influence by a superimposed magnetic field. When two electrons share an orbital space they must have opposite spin polarity. This phenomenon is dictated by the Pauli Exclusion Principal that postulates that no two electrons can occupy the same quantum state.
Spin polarity is conventionally referred to as up spin (.uparw.)+½ or down spin (.dwnarw.)−½. Shared valence electrons in the formation of chemical bonds also must have opposite spin polarity. When covalent bonds are severed as in the formation of free radicals spin polarity is preserved.
The unpaired electron in the valence orbital of a free radical in a magnetic field will precess in a manner comparable to Larmor precession described for charged particles in classic electrodynamics. Quantum precession leads to spin phase transitions between the singlet state where antiparallel spin vectors apply and triplet states where parallel spin vectors apply. The singlet state is favorable for recombination because antiparallel spin orientation is preserved and a covalent bond can be established. Triplet state configurations are unfavorable for recombination because parallel spin orientation is induced. In a magnetic field there are three triplet state configurations, which are vector quantities that due to precession in the magnetic field are no longer energy equivalent and are said to be nondegenerate.
The strength of the applied magnetic field, which maximizes the spin phase mixing effect, is dependent on the quantum state of the free radical or the system of free radicals. In general optimum phase mixing is achieved at relatively low magnetic field strengths (0.1-10.0 mTesla) within the hyperfine coupling energy levels of the radical pair.
The singlet state (S.sub.1) characterized by antiparallel spin vectors will prevail in the absence of a magnetic field when homolytic fission of a covalent bond occurs to form a free radical pair. In the presence of a magnetic field of appropriate strength, the triplet states, T.sub.−1, T.sub.0 and T.sub.−1 are equally probable energy states and are distinct and nondegenerate. The theoretic distribution between singlet and triplet states will be 25% singlet and 75% triplet. Such a distribution will theoretically increase the effective concentration of escape radicals by 75%. In experimental situations the yield is limited by non-quantum factors including viscosity effects, temperature, diffusion and bystander effects. However, increases in escape radical reactivity of 20-40% are documented in experimental systems where free radical escape reactions are measured.
U.S. Pat. Nos. 6,679,827 and 6,926,659 disclose a method for enhancing irradiation tumor treatment by creating a magnetic field that intersects with the irradiating beam in the area of the tumor. Referring to FIG. 1, showing a technique disclosed in these patents, a patient's body 10 is subjected to radiation 12 that travels through the body 10 in a first direction. A magnet 18 is oriented so as to create a magnetic field 20 in the vicinity of a tumor 22 of one milli-Tesla (mT). In another technique disclosed, shown in FIG. 2, a tumor 22 may be treated by placing radioactive strips 30 about it. Additionally, magnetic strips 32 are placed to create a magnetic field in the tumor 22. Referring to FIG. 3, in another prior art technique, a laparoscope 40 is used to introduce a magnet 42 directly into the tumor. Finally, referring to FIG. 4, a tumor may be treated by a set of radioactive beads 50 and a set of magnetic beads 52, adapted to create a magnetic field. The treatment described is time static in the sense that the irradiating beam and the magnetic field are disclosed as being simultaneous.
Much of the clinical efficacy of radiation therapy tumor treatment stems from actions by ionization-induced free radical production and changes in their combinatorial kinetics. Although it has been shown that weak magnetic fields influence free radical behavior in irradiated tissue, this knowledge has not been fully exploited in the treatment of tumors.